Project 2 Abstract: Recent results generated by the Program Project have shown that the overall survival after surgery/PDT exceeds any previous reported series. One hypothesis suggested by these data is that pPDT is inducing an immune response against the recurrent tumor and this response is inhibiting the growth of the tumor leading to prolonged survival. There is extensive animal data with PDT (without surgery) showing that, in addition to its direct cytotoxic effects, PDT also induces anti-tumor immune responses capable of affecting distant tumor. There are also a few clinical reports suggesting that PDT alone can induce anti-tumor immune responses. To date, we have no direct evidence from our patients to confirm or refute this immune hypothesis. The new randomized clinical trial design where patients will either receive surgery with pPDT or surgery alone provides a unique opportunity to test the immune response hypothesis and to define these immune responses. To do so, we will work with Project 1 and will evaluate the immune responses generated by surgery/pPDT versus surgery in patients with malignant mesothelioma (Specific Aim 1). This will be accomplished by: A) evaluating the blood leukocyte response to surgery/pPDT in comparison to surgery alone and in relationship to anti-tumor efficacy, B) evaluating anti-tumor humoral immune responses to known and unknown mesothelioma antigens induced by surgery/pPDT in comparison to surgery alone, c) evaluating anti- tumor cellular immune responses induced by surgery/pPDT in comparison to surgery alone, and d) evaluating the cytokine response to surgery/pPDT in relationship to anti-tumor efficacy. In addition to evaluating our clinical subjects, we propose one preclinical, translational aim with the goal of developing improved approaches based on exciting preliminary data. In conjunction with the Animal Core and Projects 3 and 4, we will use novel animal models of surgery/PDT to evaluate the hypothesis that the anti-tumor immune response generated by surgery/PDT can be augmented by inhibition of inflammation (COX-2 inhibitor or IL-6 inhibition) (Specific Aim 2). If supported by these aims, our goal would be to initiate a future clinical trial in which we will combine surgery/pPDT with COX-2 inhibition or anti-IL-6 antibodies.